Elevated cellular PpIX potentiates sonodynamic therapy in a mouse glioma stem cell-bearing glioma model by downregulating the Akt/NF-κB/MDR1 pathway

Abstract

Glioblastoma (GBM) has high mortality rates because of extreme therapeutic resistance. During surgical resection for GBM, 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) fluorescence is conventionally applied to distinguish GBM. However, surgical intervention is insufficient for high invasive GBM. Sonodynamic therapy (SDT) combined with low-intensity ultrasonication (US) and PpIX, as a sonosensitizer, is an emerging and promising approach, although its efficacy is limited. Based on our previous study that down-regulation of multidrug resistant protein (MDR1) in GBM augmented the anti-tumor effects of chemotherapy, we hypothesized that elevation of cellular PpIX levels by down-regulation of MDR1 enhances anti-tumor effects by SDT. In high invasive progeny cells from mouse glioma stem cells (GSCs) and a GSC-bearing mouse glioma model, we assessed the anti-tumor effects of SDT with a COX-2 inhibitor, celecoxib. Down-regulation of MDR1 by celecoxib increased cellular PpIX levels, as well as valspodar, an MDR1 inhibitor, and augmented anti-tumor effects of SDT. MDR1 down-regulation via the Akt/NF-κB pathway by celecoxib was confirmed, using an NF-κB inhibitor, CAPÉ. Thus, elevation of cellar PpIX by down-regulation of MDR1 via the Akt/NF-κB pathway may be crucial to potentiate the efficacy of SDT in a site-directed manner and provide a promising new therapeutic strategy for GBM.

Sonodynamic Therapy for the Treatment of Glioblastoma Multiforme in a Mouse Model Using a Portable Benchtop Focused Ultrasound System

“…Preliminary in vitro studies have revealed that many cancer cells are lysed by SDT treatment, though the rate of cell death is dependent on the cell line. Preliminary in vivo studies yield similar results, confirming that SDT can trigger apoptosis 5 . This protocol aims to describe effective techniques and parameters for the SDT treatment of rodent models with intracranially implanted GBM cells using a benchtop FUS research platform.…”

“…Other sonosensitizers can be substituted and tested to determine the compound most suitable for efficacy and safety. Finally, treatment was commenced 3 h post 5-ALA injection, as previous literature has shown that this is the optimal time with that injection dosage 5 .…”

A Recap of Heme Metabolism towards Understanding Protoporphyrin IX Selectivity in Cancer Cells

“…In this study, authors demonstrated that inhibition of the oncogenic Ras/MEK pathway restrained the efflux of PpIX due to ABCB1 level reduction in colon cancer cells. This was recently confirmed in a mouse malignant glioma where downregulation of MDR1 increased the cellular 5-ALA-induced PpIX level [ 43 ]. Researches on ABCB1 are very limited, hence its role remains to confirm.…”

Sonodynamic therapy and Magnetic Resonance-guided Focused Ultrasound: new therapeutic strategy in Glioblastoma

“…As just mentioned, SDT involves the application of focused ultrasound with a substance that sensitizes cells to the destroying effects of sound, called sonosensitizer. It includes both ultrasonication, via non-invasive lowintensity ultrasound penetrating soft tissues and focus on a speci c site, and sonosensitizers, which embrace nontoxic chemical agents such as 5-ALA, ATX-70, Hypocrellin, Rose Bengal and many others [64-66]; some of these compounds are commonly used in glioma surgery to intraoperatively visualize the tumor and can be employed to induce cytotoxic effects to neoplastic cells when subjected to a speci c acoustic eld [31,39,67]. The advantage of this technique is to minimize adverse events and maximizing on-target responses.…”